Heterocycle-coupled substituted pyrrolo[3,2-c]pyridin-2-carboxylic acids

ABSTRACT

A compound of formula ##STR1## in which A represents S; 
     R 1  is selected from the group consisting of OH, (C 1  -C 12 )alkyl, (C 1  -C 12 )alkoxy, benzyloxy, phenyl, benzyl (C 1  -C 4 )alkyl NZ 1  Z 2 , and NZ 1  Z 2  ; 
     R 2  is selected from the group consisting of OH, SH, (C 1  -C 4 )alkoxy, (C 1  -C 4 )alkylthio, and NZ 1  Z 2  ; 
     R 3  is selected from the group consisting of H, (C 1  -C 4 )alkyl, (C 1  -C 4 )alkylthio, (C 1  -C 4 )alkoxy, phenyl, and benzyl; 
     B is selected from the group consisting of phenyl; pyridyl; phenyl substituted by one or more groups selected from halo, (C 1  -C 6 )alkyl, (C 1  -C 6 )alkoxy, CF 3 , CH 2  NZ 1  Z 2 , and NZ 1  Z 2  wherein Z 1  and Z 2  are selected, independently of each other, from the group consisting of H, (C 1  -C 6 )alkyl, formyl, and benzyl or --NZ 1  Z 2  is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholino, hexahydroazepino, ##STR2## piperazino, piperazino substituted in position 4 by (C 1  -C 8 )alkyl, benzyl or diphenylmethyl; and pyridyl substituted by one or more groups selected from halo, (C 1  -C 6 )alkyl, (C 1  -C 6 )alkoxy, CF 3 , CH 2  NZ 1  Z 2 , and NZ 1  Z 2  wherein Z 1  and Z 2  are selected, independently of each other, from the group consisting of H, (C 1  -C 6 )alkyl, formyl, and benzyl, or NZ 1  Z 2  is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholino, hyxahydroazepino, ##STR3## piperazino, and piperazino substituted in position 4 by (C 1  -C 8 )alkyl, benzyl or diphenylmethyl; or its salt with an acid or a base.

This application is a divisional of Ser. No. 08/109,073, filed Aug. 19, 1993, now U.S. Pat. No. 5,360,799.

The present invention relates to substituted pyrrolo[3,2-c]pyridin-2-carboxylic acids coupled to an aromatic heterocycle and to their sulphur-containing analogs, to processes for their preparation and to the pharmaceutical compositions which comprise them as active ingredients.

These new compounds are especially inhibitors of the effect of biological oxygenated free radicals, such as the superoxide anion O₂.sup..- or the hydroxyl radical; it is known that when these free radicals, necessarily present in man and animals, are formed in an amount which is too great for them to be rapidly removed by the usual physiological mechanisms, they attack and destroy cell constituents, such as nucleic acids, proteins or walls. The tissues affected are very diverse and many authors regard free radicals as the source of many degenerative diseases ranging from inflammatory or autoimmune diseases to respiratory insufficiency and cardiac, cerebral or intestinal ischemias; they are also implicated in the degenerative phenomena of ageing.

The compounds of the invention correspond to the formula I: ##STR4## in which R₁ represents OH, (C₁ -C₁₂)alkyl, (C₁ -C₁₂)alkoxy, benzyloxy, phenyl, benzyl, (C₁ -C₄)alkylNZ₁ Z₂ or NZ₁ Z₂ ;

R₂ represents OH, SH, (C₁ -C₄)alkoxy, (C₁ -C₄)alkylthio or NZ₁ Z₂ ;

R₃ represents H, (C₁ -C₄)alkyl, (C₁ -C₄)alkylthio, (C₁ -C₄)alkoxy, phenyl or benzyl;

A represents S, and in this case R represents nothing, or

A represents N and R represents H or (C₁ -C₄)alkyl which can be substituted by phenyl or NZ₁ Z₂ ;

B represents an aromatic ring coupled to the pyridyl ring, and can be phenyl, pyridyl or thienyl to form respectively a pyrrolo[3,2-c]quinoline, pyrrolo[3,2-c]naphthyridine or pyrrolo[3,2-c]thienopyridine tricyclic group when A represents N, or a thieno[3,2-c]quinoline, thieno[3,2-c]naphthyridine or thieno[3,2-c]thienopyridine group when A represents S;

B is optionally substituted by one or more groups chosen from halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, CF₃, CH₂ NZ₁ Z₂ or NZ₁ Z₂ ; and

Z₁ and Z₂ represent, independently of each other, H, (C₁ -C₆)alkyl, formyl or benzyl, or they form, with the nitrogen atom to which they are attached, a saturated heterocycle, optionally interrupted by a heteroatom chosen from O, S or N, it being possible for the latter to be substituted by (C₁ -C₈)alkyl, benzyl, phenyl or diphenylmethyl, with the proviso that when A is S, R is nothing, R₁ is --OCH₃, R₃ is H and B is thienyl, R₂ cannot be --OH or --O--CH₃ ;

as well as the salts of these compounds with an acid or a base.

The alkyl and alkoxy groups can be linear or branched or form a ring, especially cyclopentyl or cyclohexyl.

F or Cl are preferred as halogen.

When the group NZ₁ Z₂ represents a saturated heterocycle, it can be a pyrrolidinyl, piperidinyl, morpholino, hexahydroazepino, piperazino or piperazino substituted in position 4 by (C₁ -C₈)alkyl, benzyl, phenyl or diphenylmethyl.

Among the compounds of the invention, the preferred ones are those of formula II: ##STR5## in which R, R₁, R₂ and R₃ are as in Formula I and D represents N or better C, whereas R₄ represents NZ₁ Z₂, and more particularly those in which R₄ is at position 8, ortho to D, and, among the last ones, preferably the compounds in which R₂ is NZ'₁ Z'₂, Z'₁ and Z'₂ representing, independently of each other, H or (C₁ -C₆)alkyl. Among the latter compounds, those for which COR₁ is in addition an ester group are preferred.

Another group of preferred compounds consist of the compounds of formula II in which R, R₁, R₂ and R₃ are as in the formula I and D represents N, whereas R₄ represents NZ₁ Z₂, Z₁ and Z₂ representing, independently of each other, H or (C₁ -C₆)alkyl or Z₁ and Z₂ forming, with the nitrogen atom to which they are attached, a piperazino group which can be substituted on the nitrogen by (C₁ -C₈)alkyl, phenyl or diphenylmethyl.

The compounds of formula I can be prepared, by using processes whose principles are known in themselves, from suitably substituted quinolines, naphthrydines or thienopyridines.

According to one process, the compound of formula ##STR6## in which A, B, R, R₁ and R₃ have the same meaning as in the formula I, and Z represents an alkoxycarbonyl or cyano group, is cyclised, in a Dieckmann reaction, to give a compound of formula I in which R2 represents OH, when Z represents an alkoxycarbonyl group, or to give a compound of formula I in which R₂ represents NH₂, when Z represents a cyano group.

According to another process, the compounds of formulae ##STR7## in which A, B, R, R₁ and R₃ have the same meaning as in the formula I, X represents Cl and Z represents an alkoxycarbonyl or cyano group, are heated, in the presence of phenol, to form a compound of formula I in which R₂ represents OH, when Z represents an alkoxycarbonyl group, or to form a compound of formula I in which R₂ represents NH₂, when Z represents a cyano group.

In order to produce the substituted pyrroles of formula I in which A is N and R₂ is OH, an amine of formula III:

    RNHCH.sub.2 COR.sub.1                                      III

in which R and R₁ have the same meaning as in the formula I, with the exception of R₁ ═OH, is reacted with the compound of formula IV: ##STR8## in which X represents Cl or Br, R₅ represents (C₁ -C₃)alkyl and B and R₃ have the same meaning as in the formula I, to produce the compound of formula V: ##STR9## in which R, R₁, R₃, R₅ and B are as in the formulae III and IV, which compound is cyclised in a Dieckmann reaction by reacting with an organic or inorganic base, such as (C₂ H₅)₃ N, C₂ H₅ ONa, t-C₄ H₉ ONa, NaH or KOH, in a nonaqueous solvent, such as an alcohol, an ether such as dioxane, or dimethylformamide, preferably at a temperature between 0° C. and 80° C.

In order to obtain the substituted pyrroles of formula I in which A is N and R₂ is NH₂, an amine of formula III is reacted with a compound of formula VI: ##STR10## in which X is Cl or Br, and R₃ and B have the same meaning as in formula I, to produce the compound of formula VII: ##STR11## in which R, R₁, R₃ and B are as in the formula I, which compound is cyclised by a Dieckmann reaction.

It is also possible to directly obtain the compounds of formula I by reacting coupled pyridines of formula IV or VI and amines of formula III in the presence of one molar equivalent of phenol and one molar equivalent of an organic or inorganic base, generally without a solvent, at a temperature greater than approximately 100° C.

When, in the compound of formula I which it is desired to obtain, R is other than H, it is possible to substitute the nitrogen of the pyrrole of the compound of formula I in which R═H by reacting with a halide RX in the presence of a strong base, such as NaH, in a polar aprotic solvent or in a 2-phase medium in the presence of a phase transfer catalyst.

In order to obtain the thiophene compounds of formula I in which A represents S, a substituted compound of formula HS--CH₂ --COR₁, (in place of the amine RNHCH₂ --COR₁ of formula III) is reacted with the compound of formula IV or with that of formula VI.

In order to obtain the compounds of formula I in which R₁ is OH, the corresponding esters in which R₁ is alkoxy, for example tert-butoxy, are hydrolysed, preferably in aqueous acidic medium, whereas, in order to obtain the compounds in which R₁ is NZ₁ Z₂, it is possible to react the amine HNZ₁ Z₂ with the corresponding ester under the usual conditions for producing secondary or tertiary amides; however, it is preferable to directly react the amide of formula III: RNHCH₂ --CONZ₁ Z₂ with the compound of formula IV.

The compounds of formula I in which R₂ represents alkoxy are prepared from those in which R₂ is OH by reacting with a suitable alkyl halide in the presence of a strong base, such as NaH or C₂ H₅ ONa, under the usual conditions for production of an ether, optionally after protecting the nitrogen of the pyrrole.

The compounds of formula I in which R₂ represents NZ₁ Z₂ with Z₁ and Z₂ other than H are prepared by known methods for substituting aliphatic primary amines.

The coupled pyridines of formulae IV or VI are prepared from amines BNH₂ by conventional methods described for instance in J. Med. Chem., 22, 816-823 (1979) via the corresponding hydroxylated derivatives of formulae IV or VI in which X represents OH, which give, for example, the compound in which X═Cl by reacting with POCl₃.

The compounds of formula VIII: ##STR12## in which Z represents an ethoxycarbonyl or cyano group, can be prepared according to the following reaction scheme: ##STR13##

The first stage is generally carried out without a solvent whereas the cyclisation is carried out in a solvent with a very high boiling point, Dowtherm® or diphenyl ether.

Certain of the substituted compounds of formulae V and VII which derive therefrom have been described in EP-A-0,205,362 and EP-A-0,346,208. The others can be prepared by analogous procedures. A process for the preparation of amino ketones of formula III is described especially in Tetrahedron Letters, 25, 2977-2980 (1984); amino esters are well known compounds.

The pharmaceutical compositions which contain, as active ingredients at least one compound of formula I or one of their salts with a pharmaceutically acceptable acid are also provided by the invention. These compositions may contain the carrier conventionally used for formulating pharmaceutical compositions which can be administered orally or rectally or by intravenous or intramuscular injection.

For oral administration, in the form of tablets, gelatin capsules or granules, or even of syrups the unit dose will be between 5 and 200 mg, according to the potency of the compound, the nature of the disease to be treated and the condition of the patient.

For parenteral administration, water-soluble salts of the compounds of formula I will preferably be used or, failing that, products known as solubilisation adjuvants will be introduced into the composition; the unit dose will then be between 1 mg and 30 mg for a volume of 1 to 5 cm³.

The pharmaceutical compositions according to the invention will be administered preventively or curatively in man or animals to reduce or suppress the toxic consequences of the presence of oxygenated free radicals and to treat the disorders which result therefrom. The latter affect varied organs and the compositions of the invention could be used in the treatment of rheumatic diseases such as arthritis, of pulmonary diseases, of cardiovascular diseases such as arteriosclerosis or the consequences of ischemias, of eye disorders such as cataracts, or even cerebral damages, including Alzheimer's disease. For information on the many potential therapeutic uses of these compounds, reference can be made to recently published books and articles, especially to: "Free Radicals in Molecular Biology, Ageing and Disease", published by Raven Press (New York), or to "CRC Handbook of Free Radicals and Antioxidants in Biomedicine", published by CRC Press (Boca Raton, Fla., U.S.A.).

Nevertheless, the therapeutic uses of the compounds according to the invention should not be limited to the indications mentioned; the compounds could be used preventively or curatively in any situation where an excess of oxygenated free radicals can disturb the normal physiological state.

The activity of compounds according to the invention on biological oxygenated free radicals has been established in vitro and in vivo.

In vitro, their action has been studied on the production of malondialdehyde during the decomposition of the endoperoxides resulting from the oxidation, in the presence of iron salt, of the polyunsaturated fatty acids contained in the phospholipids of cell walls. A conventional method, described for instance in CRC Handbook of Methods for Oxygen Radical Research, pp. 203-207 (1985), CRC Press, Boca Raton (Fla., U.S.A.) was used.

In vivo, it was shown that these compounds counteracted the toxic effects of potassium cyanide in mice and reduced hyperglycaemia due to the administration of alloxan in mice.

In effect, it is accepted that, during poisoning with KCN, the cell disorders and the nervous disorders are the consequence of a rise in intracellular calcium, but also of the oxidation of lipid walls of brain cells, and the antagonism of the toxicity of KCN has been used, especially in J. Med. Chem., 33, 1145-1151 (1990) and Arzneim. Forsch., Drug Research 39, 445-450 (1989), to point out an antioxidising activity in the brain.

Moreover, it is known that the administration of alloxan to an animal results in hyperglycaemia due to the destruction of the beta cells of the pancreas by oxygenated radicals, whose formation is triggered by the presence of alloxan, and it has been shown, especially in Biochem. Pharmacol., 34, 3601-3603 (1985) and Fundamental Clinical Pharmacology, 3, 323-328 (1989), that several scavengers of oxygenated free radicals counteract this hyperglycaemia.

In the malondialdehyde test, the 50% inhibitory concentration (IC₅₀) is, for the compounds of the invention, generally between 0.1 μM and 10 μM. In the potassium cyanide test, the effective dose 50 (ED₅₀) is between approximately 2 mg/kg and 30 mg/kg intravenously in mice, whereas, in the alloxan test, it is between 0.1 mg/kg and 10 mg/kg intravenously in mice.

Examples of the invention are described in the following with, for some of them, their detailed method of preparation.

EXAMPLE 1 Ethyl 1H-3-hydroxypyrrolo[3,2-c]quinoline-2-carboxylate (A=N; B=C₆ H₄ ; R=H; R₁ =OC₂ H₅ ; R₂ =OH; R₃ =H)

6 g of ethyl 3-ethoxycarbonyl-4-quinolyl-2-amino acetate (M.p. =114° C.) in solution in 80 ml of dry toluene are added, over 30 minutes, to 2.5 g of potassium tert-butoxide in 80 ml of anhydrous tert-butanol.

The mixture is stirred for 10 hours under nitrogen and then poured into 200 ml of ice-cold water. An N aqueous HCl solution is introduced into the basic aqueous phase to a pH of 8. The precipitate which appears is filtered, washed with absolute ethanol and then recrystallised from a dimethylformamide/ethanol (50/50) mixture. The crystals are dried at 130° C. under vacuum. Yield 30% - M.p.>250° C.

EXAMPLE 2 8-Chloro-2-(N,N-dipropylcarbamoyl)-3-hydroxy-1-methylpyrrolo[3,2-c]quinoline (A=N; B=8-ClC₆ H₃ ; R=CH₃ ; R₁ =N(C₃ H₇)₂ ; R₂ =OH, R₃ =H)

0.66g of potassium tert-butoxide is added portionwise to 1.94 g of ethyl 6-chloro-4-(N-(N,N-dipropylcarbamoylmethyl)-N-methylamino)quinoline-3-carboxylate in solution in 30 ml of tetrahydrofuran; the mixture is stirred for 2 hours and then the whole is concentrated to dryness. The precipitate is solubilised in water; the aqueous phase is acidified by addition of an N aqueous HCl solution to a pH of 7. The expected product precipitates; it is purified by recrystallisation from ethyl acetate; M.p.=180° C. (Yield 58%).

EXAMPLE 3 8-(N,N-diethylamino)-2-(N,N-dipropylcarbamoyl)-3-hydroxy-1-methylpyrrolo[3,2-c]quinoline (A=N; B=8-(C₂ H₅)₂ NC₆ H₃ ; R=CH₃ ; R₁ =N(C₃ H₇)₂ ; R₂ =OH)

4.42 g of ethyl 6-(N,N-diethylamino)-4-(N-(N,N-dipropylcarbamoylmethyl)-N-methylamino)quinoline-3-carboxylate, in solution in 100 ml of toluene, are added under nitrogen to a solution of 20 ml of tert-butanol and 1.12 g of potassium tert-butoxide. The mixture is stirred overnight at room temperature and then poured into 250 ml of ice-cold water. The aqueous solution is washed with ether and acidified with dilute HCl to a pH of 7.1-7.2. The pale-yellow precipitate obtained is recrystallised from ethyl acetate; M.p.=224° C. (Yield 40%).

EXAMPLE 4 Ethyl 1H-8-chloro-3-hydroxypyrrolo[3,2-c][1,5]naphthyridine-2-carboxylate ##STR14## a) Ethyl(6-chloro-3-ethoxycarbonyl-1,5-naphthyridine-4-yl-2-amino)acetate.

5.2 ml of triethylamine are added dropwise to 5.1 g of 4,6-dichloro-3-ethoxycarbonyl-1,5-naphthyridine, in solution in 140 ml of ethanol, and 2.65 g of the hydrochloride of the ethyl ester of glycine.

On completion of addition, the reaction mixture is maintained at the reflux temperature of the ethanol for 2 hours and is then brought to dryness; the residue is dissolved in methylene chloride and the organic phase is washed with water and then dried. After removing the solvent, the product is recrystallised from ethanol. M.p.=140° C. (Yield 46%).

b) 3.84 g of the above naphthyridine, in solution in 45 ml of toluene and 40 ml of dimethylformamide, are added dropwise, under a slight nitrogen stream, to 1.37 g of potassium tert-butoxide in solution in 25 ml of tert-butanol. The solution is stirred at room temperature overnight and the reaction mixture is then poured into 150 ml of a water/ice mixture. After neutralisation of the aqueous phase, the expected product precipitates. M.p.=250° C. (Yield 59%).

EXAMPLE 5 7-(N,N-dipropylcarbamoyl)-6-hydroxy-8-methylpyrrolo[3,2-d]thieno[3,2-b ]pyridine ##STR15## a) Ethyl 7-(N-(N,N-dipropylcarbamoylmethyl)-N-methylamino)thieno[3,2-b]pyridine-6-carboxylate.

3 g of ethyl 7-chlorothieno[3,2-b]pyridine-6-carboxylate (M.p.=84° C.), prepared by reacting POCl₃ with ethyl 7-hydroxythieno[3,2-b]pyridine-6-carboxylate, obtained by the method described in J. Chem. Res. (M), p. 4701 (1978), 2.6 g of N,N-dipropyl-2-(methyl-amino)acetamide and 2.3 ml of triethylamine in 70 ml of toluene are maintained at the reflux temperature of the mixture for 20 hours. The toluene phase is washed with water and then concentrated to dryness. The expected product is purified by chromatography on silica gel, the eluent being isopropyl ether; it is a yellow oil. (Yield=49%).

b) 2.3 g of the above product, in solution in 50 ml of dry toluene, are introduced into 20 ml of tert-butanol containing 0.8 g of potassium tert-butoxide. After 3 hours at room temperature, the mixture is poured into 300 ml of cold water. The separated aqueous phase is filtered and acidified by addition of a 0.1N aqueous HCl solution to a pH of 7.2. The precipitate formed is filtered and then recrystallised from ethyl acetate. M.p.=120° C. (Yield 40%).

EXAMPLE 6 Ethyl 1H-3-amino-8-(N,N-diethylamino)-6-methyl-pyrrolo[3,2-c]quinoline-2-carboxylate ##STR16## a) Ethyl 3-[4-(N,N-diethylamino)-2-methylanilino]-2-cyanoacrylate

A mixture of 85 g of 4-(N,N-diethylamino)-2-methylaniline and 67 g of 2-cyano-3-ethoxyacrylate is heated for 2 hours at 140°-150° C. the ethanol being distilled off as it is formed. After recrystallisation from cyclohexane, the desired product is obtained. M.p.=128° C. (Yield 93%).

b) 3-cyano-6-(N,N-diethylamino)-4-hydroxy-8-methylquinoline

60 g of the above product are introduced into 645 ml of diphenyl ether, maintained at 200° C., and then the mixture is heated to 257° C. over 4 hours before distilling approximately 400 ml of diphenyl ether. After cooling, the expected product is precipitated by addition of petroleum ether; the solid is washed with ethyl ether and then with hot ethyl acetate to give a brown solid. M.p.≧250° C. with a yield of 43%.

c) 4-Chloro-3-cyano-6-(N,N-diethylamino)-8-methylquinoline

A mixture of 12 g of the product obtained in b) and 70 ml of phosphoryl chloride is heated for 1 h 30° at 70° C. After evaporation under vacuum of the excess acid chloride, the mixture is poured into water, neutralised and the expected chlorinated product is extracted with methylene chloride. It is purified by filtration through silica gel in a cyclohexane/ethyl acetate (5/5) mixture and recrystallised from petroleum ether. M.p.=115° C. (Yield 44%).

d) A mixture of 5.8 g of the product obtained in c), 4.2 g of phenol, 4.2 g of the hydrochloride of the ethylester of glycine and 8.6 ml of triethylamine are maintained for 2 hours at 140° C.

Water is then added to the mixture, acidification is carried out, the mixture is washed with ethyl ether and then the aqueous phase is neutralised before being extracted with methylene chloride. The residue obtained by evaporation of the solvent is washed with isopropyl ether and then recrystallised from ethyl acetate. M.p.=256° C. (Yield 51%).

EXAMPLE 7 Ethyl 3-amino-8-(N,N-diethylamino)-1,6-dimethylpyrrolo[3,2-c]quinoline-2-carboxylate ##STR17##

A mixture of 3,4 g of 4-chloro-3-cyano-6-(N,N-diethylamino)-8-methylquinoline, 2.6 g of phenol and 2.8 g of the hydrochloride of the ethyl ester of sarcosine in 5.1 ml of triethylamine is maintained for 2 hours at 140° C.

After acidification by addition of 0.1N HCl and washing with ethyl ether, the aqueous phase is neutralised and then extracted with methylene chloride. After drying and evaporation of the organic solvent, the residue is chromatographed on silica gel, the eluent being ethyl acetate. The expected product is recrystallised from isopropyl ether. M.p.=209° C. (Yield 36%).

EXAMPLE 8 Ethyl 1H-3-amino-8-(N,N-diethylamino)-4-methylpyrrolo[3,2-c]quinoline-2-carboxylate ##STR18## a) An equimolecular mixture of 4-(N,N-diethylamino)aniline and ethyl 2-cyano-3-ethoxy-3-methylacrylate, prepared by applying the method described in J. Org. Chem., 27, 1371-1374, (1961), is heated for 2 hours at 140° C.

The anilinoacrylate formed is then cyclised in solution in diphenyl ether by heating at 260° C. for 5 hours 30. After the usual treatment, 3-cyano-6-(N,N-diethylamino)-4-hydroxy-2-methylquinoline is obtained with a yield of 49%. M.p.>250° C.

b) 10 g of the quinoline obtained in a) are heated at 70° C. for 1 hour 30 in 50 ml of phosphoryl chloride. After evaporation to dryness, addition of water and neutralisation, extraction is carried out with ethyl acetate; the organic phase is filtered through silica gel to give the desired product with a yield of 53%. M.p.=114° C.

c) 5.8 g of the above chlorinated derivative with 4.17 g of the hydrochloride of the ethyl ester of glycine, 4 g of phenol and 8.3 ml of triethylamine are maintained for 2 hours at 140° C. After acidification and washing with ethyl ether, the aqueous phase is neutralised and then extracted with methylene chloride. The expected product, recrystallised from isopropyl ether, melts at 250° C. (Yield 37%).

EXAMPLE 9 8-(N,N-Diethylamino)-2-(N,N-dipropylcarbamoyl)-3-ethoxy-1-methylpyrrolo[3,2-c]quinoline (A=N; B=8-(C₂ H₅)₂ NC₆ H₃ ; R=CH₃ ; R₁ =N(C₃ H₇)₂ ; R₂ =OC₂ H₅ ; R₃ =H).

A solution of 2 g of 8-(N,N-diethylamino)-2-(N,N-dipropylcarbamoyl)-3-hydroxy-1-methylpyrrolo[3,2-c]quinoline (M.p.=224° C.) in 30 ml of dry dimethyl formamide are introduced, under nitrogen, into 10 ml of the same solvent containing 0.24 g of NaH, and then the mixture is heated at 60° C. for 30 minutes before adding dropwise 0.4 ml of ethyl iodide in solution in 10 ml of solvent. The mixture is heated for 2 hours at 70° C. and then poured into 600 ml of water at around 10° C. By extracting with methylene chloride, there are obtained 2.5 g of crude product which product is purified by chromatography on silica gel, the eluent being ethyl acetate. The oil obtained is dissolved in ethyl ether and a hydrochloric acid solution, in the same solvent, is added to precipitate the hydrochloride of the desired product, with a yield of 65%. M.p.=170° C.

EXAMPLE 10 Ethyl 1H-3-amino-8-(N,N-diethylamino)-4-(methylthio)pyrrolo[3,2-c]quinoline-2-carboxylate ##STR19## a) Ethyl 3-[4-(N,N-diethylamino)anilino]-2-cyano-3-(methylthio)acrylate

21.7 g of ethyl 2-cyano-3,3-bis(methylthio)acrylate and 16.5 g of 4-(N,N-diethylamino)aniline are heated for 2 hours at 120° C. The residue is purified by chromatography on a silica column, the eluent being a toluene/ethanol (97/3) mixture; the expected product is recrystallised from cyclohexane. M.p.=100° C. (Yield 81%).

b) 6-(N,N-diethylamino)-3-cyano-4-hydroxy-2-(methylthio)quinoline

26 g of the product obtained in a) are cyclised by heating in Dowthern A, a mixture of 275 g of biphenyl and 707 ml of diphenyl ether, at the reflux temperature of the mixture for 45 minutes. The solvent is then removed by distillation under reduced pressure. The residue, after washing with petroleum ether, is purified by chromatography on a silica column, the eluent being a toluene/ethanol (95/5) mixture.

c) 6-(N,N-diethylamino)-4-chloro-3-cyano-2-(methylthio)quinoline

100 ml of POCl₃ and 5 g of the oil obtained in b) are heated at reflux for 1 hour. The excess phosphorous oxychloride is removed, the residue is dissolved in dichloromethane and the organic phase is washed with an aqueous NaOH solution and then with water to neutrality; after drying, the organic phase is concentrated to dryness and the residue is purified by chromatography on a silica column (99/1 toluene/ethanol eluent).

After recrystallisation from cyclohexane, the desired product melts at 146° C. (Yield 72%).

d) Ethyl[6-(N,N-diethylamino)-3-cyano-2-methylthio-4-quinolyl]aminoacetate.

2 g of the compound obtained in c), 1 g of the hydrochloride of the ethyl ester of glycine, 2 ml of triethylamine and 100 ml of ethanol are heated at reflux in ethanol for 12 hours before addition of the same amount of hydrochloride and 2 ml of triethylamine. Reflux is maintained for a further 20 hours.

The mixture, after concentration to dryness, is taken up in dichloromethane and the organic phase is washed with water. After removing the solvent, the residue is chromatographed on a silica column (80/20 cyclohexane/ethyl acetate eluent). The expected product is obtained with a yield of 55%, which product melts at 130° C.

e) 1.5 g of this compound are cyclised in 60 ml of ethanol containing sodium ethoxide, obtained with 0.1 g of Na, at room temperature. After stirring for 4 hours, the mixture is concentrated to dryness and 100 ml of water are poured onto the residue. The precipitate is isolated. M.p.=198° C. (Yield 30%).

The melting points of pyrrole derivatives according to the invention, prepared by applying one of the above methods, are mentioned in the following Tables 1 and 2.

                                      TABLE 1                                      __________________________________________________________________________      ##STR20##                                                                                                                  M.p. °C.                   Example                                                                             R    R.sub.1  R.sub.2 R.sub.3                                                                           R.sub.4    R.sub.5                                                                            (salt)                            __________________________________________________________________________     11   H    OC.sub.2 H.sub.5                                                                        OH      H  7-Cl       H   >250                              12   H    OC.sub.2 H.sub.5                                                                        OH      H  8-Cl       H   >250                              13   H    OC.sub.2 H.sub.5                                                                        OH      H  8-CH.sub.3 H   >250                              14   H    OC.sub.2 H.sub.5                                                                        OH      H  7-CF.sub.3 H   >250                              15   H    OC.sub.2 H.sub.5                                                                        OH      H  7-F        H   >250                              16   CH.sub.3                                                                            OC.sub.2 H.sub.5                                                                        OH      H  H          H   230                                                                            (HCl)                             17   CH.sub.3                                                                            OC.sub.2 H.sub.5                                                                        OH      H  8-Cl       H   180                               18   CH.sub.3                                                                            OC.sub.2 H.sub.5                                                                        OH      H  7-CF.sub.3 H   170                               19   H    OC.sub.2 H.sub.5                                                                        OH      CH.sub.3                                                                          H          H   241                               20   H    OC.sub.2 H.sub.5                                                                        OH      CH.sub.3                                                                          8-Cl       H   >250                              21   H    OC.sub.2 H.sub.5                                                                        OH      C.sub.6 H.sub.5                                                                   8-Cl       H   >250                              22   H    OC.sub.2 H.sub.5                                                                        OH      H  8-N(C.sub.2 H.sub.5).sub.2                                                                H   160                               23   H    OC.sub.2 H.sub.5                                                                        OH      H                                                                                  ##STR21## H   158 (HCl)                         24   H    OC.sub.2 H.sub.5                                                                        OH      H                                                                                  ##STR22## H   163                               25   CH.sub.2 C.sub.6 H.sub.5                                                            OC.sub.2 H.sub.5                                                                        OH      H  H          H   230                                                                            (HCl)                             26   CH.sub.2 C.sub.6 H.sub.5                                                            OC.sub.2 H.sub.5                                                                        OH      H  8-Cl       H   188                               27   CH.sub.3                                                                            OC.sub.2 H.sub.5                                                                        OH      H  8-N(C.sub.2 H.sub.5).sub.2                                                                H   168                                                                            (HCl)                             28   CH.sub.3                                                                            OC.sub.2 H.sub.5                                                                        OH      H                                                                                  ##STR23## H   176                               29   CH.sub.3                                                                            OC.sub.2 H.sub.5                                                                        OH      H                                                                                  ##STR24## H   158                               30   H    CH(C.sub.3 H.sub.7).sub.2                                                               OH      H  8-Cl       H   >250                              31   H    CH(C.sub.3 H.sub.7).sub.2                                                               OH      H  8-N(C.sub.2 H.sub.5).sub.2                                                                H   >250                              32   H    CH(C.sub.3 H.sub.7).sub.2                                                               OH      H                                                                                  ##STR25## H   171                               33   H    C.sub.6 H.sub.5                                                                         OH      H  8-Cl       H   >250                              34   H    C.sub.6 H.sub.5                                                                         OH      H  8-N(C.sub.2 H.sub.5).sub.2                                                                H   >250                              35   H    O(CH.sub.2).sub.11 CH.sub.3                                                             OH      H  7-CF.sub.3 H   >250                              36   CH.sub.2 C.sub.6 H.sub.5                                                            OC(CH.sub.3).sub.3                                                                      OH      H  H          H   212                               37   CH.sub.3                                                                            O(CH.sub.2).sub.2 N(C.sub.2 H.sub.5).sub.2                                              OH      H  8-Cl       H   100                               38   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H  8-Cl       H   >250                              39   H    CH(C.sub.3 H.sub.7).sub.2                                                               NH.sub.2                                                                               H  S-N(C.sub.2 H.sub.5 ).sub.2                                                               H   >250                              40   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                H   232                               41   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                7-CF.sub.3                                                                         180                               42   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CF.sub.3                                                                         >250                              43   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               C.sub.2 H.sub.5                                                                   8-N(C.sub.2 H.sub.5).sub.2                                                                H   224                               44   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H  7-N(CH.sub.3).sub.2                                                                       H   >250                              45   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H                                                                                  ##STR26## H   >250 (2HCl)                       46   H    OCH.sub.2 C.sub.6 H.sub.5                                                               NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                H   240                               47   H    OC(CH.sub.3).sub.3                                                                      NH.sub.2                                                                               C.sub.2 H.sub.5                                                                   8-N(C.sub.2 H.sub.5).sub.2                                                                H   240                               48   CH.sub.3                                                                            OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                H   169                               49   CH.sub.3                                                                            OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               C.sub.2 H.sub.5                                                                   8-N(C.sub.5 H.sub.5).sub.2                                                                H   122                               50   CH.sub.3                                                                            OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CF.sub.3                                                                         250                               51   H    OCH(CH.sub.3).sub.2                                                                     NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         >250                                                                           (HCl)                             52   H    OCH.sub.2 CH(CH.sub.3).sub.2                                                            NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         218                               53   H    OCH(CH.sub.3).sub.2                                                                     NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                H   >250                              54   H    OC.sub.5 H.sub.11                                                                       NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         197                                                                            (0.5H.sub.2 0)                    55   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.-                                                                6-CH.sub.3                                                                         238                                                             (C.sub.4 H.sub.9)                                                                             (H.sub.2 O)                       56   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         >250                              57   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         210                               58   H    OCH(C.sub.2 H.sub.5).sub.2                                                              NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         225                               59   H    OCH(CH.sub.3).sub.2                                                                     NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         246                               60   H    OCH(CH.sub.3)(C.sub.2 H.sub.5)                                                          NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         228                               61   H    OCH(CH.sub.3)(C.sub.3 H.sub.7)                                                          NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         198                               62   H                                                                                    ##STR27##                                                                              NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         222 (0.5H.sub.2 O)                63   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                7-F 258                               64   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H  S-N(C.sub.2 H.sub.5).sub.2                                                                7-F 228                               65   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                7-Cl                                                                               254                               66   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                7-Cl                                                                               185                                                                            (0.5H.sub.2 O)                    67   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                6-CF.sub.3                                                                         175                               68   C.sub.3 H.sub.7                                                                     OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         136                               69   H    OCH(CH.sub.3).sub.2                                                                     NH.sub.2                                                                               C.sub.2 H.sub.5                                                                   S-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         217                               70   H    OCH.sub.2 CIH5                                                                          NH.sub.2                                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         218                                                                            (0.5H.sub.2 O)                    71   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H                                                                                  ##STR28## 6-CH.sub.3                                                                         >250 (0.5H.sub.2 O)               72   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               H                                                                                  ##STR29## 6-CH.sub.3                                                                         >250 (2H.sub.2 O)                 73   H    OCH(CH.sub.3).sub.2                                                                     NH.sub.2                                                                               CH.sub.3                                                                           ##STR30## 6-CH.sub.3                                                                         255                               74   H    OC.sub.2 H.sub.5                                                                        NH.sub.2                                                                               CH.sub.3                                                                          8-OC.sub.5 H.sub.11                                                                       H   244                               75   H    OC.sub.2 H.sub.5                                                                        NHCH.sub.3                                                                             H  8-N(C.sub.2 H.sub.5).sub.2                                                                H   224                               76   H    OC.sub.2 H.sub.5                                                                        NHCH.sub.3                                                                             H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         134                               77   H    OC.sub.2 H.sub.5                                                                        NHCH.sub.3                                                                             CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                H   220                               78   H    OC.sub.2 H.sub.5                                                                        NHC.sub.2 H.sub.5                                                                      H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         226                               79   H    OC.sub.2 H.sub.5                                                                        NHC.sub.3 H.sub.7                                                                      H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         194                               80   H    OCH(CH.sub.3).sub.2                                                                     N(C.sub.2 H.sub.5).sub.2                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         182                               81   H    OC.sub.2 H.sub.5                                                                        N(C.sub.3 H.sub.7).sub.2                                                               H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         184                               82   H    OC.sub.2 H.sub.5                                                                        N(C.sub.2 H.sub.5)(CHO)                                                                CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                H   200                               83   H    OCH(CH.sub.3).sub.2                                                                     N(C.sub.2 H.sub.5)(CHO)                                                                CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         100                                84a CH.sub.2 C.sub.6 H.sub.5                                                            OC.sub.2 H.sub.5                                                                        NHCH.sub.2 C.sub.6 H.sub.5                                                             H  8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         182                                84b H                                                                                    ##STR31##                                                                              NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         188                                84c H                                                                                    ##STR32##                                                                              NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                6-CH.sub.3                                                                         210                                 84d                                                                               H                                                                                    ##STR33##                                                                              NH.sub.2                                                                               CH.sub.3                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                7-F >250                               84e H    OCH(CH.sub.3).sub.2                                                                     NH.sub.2                                                                               CH.sub.3                                                                           ##STR34## 6-CH.sub.3                                                                         250                               __________________________________________________________________________

                                      TABLE 2                                      __________________________________________________________________________      ##STR35##                                                                                                            M.p. °C.                         Example                                                                             R        R.sub.1                                                                              R.sub.2                                                                            R.sub.3                                                                            R.sub.4                                                                               R.sub.5                                                                            (salt)                                  __________________________________________________________________________      85  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  SCH.sub.3                                                                          H      H   165                                      86  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H   H      H   210                                      87  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H   7-CF.sub.3                                                                            H   228                                      88  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H   8-CH.sub.3                                                                            H   233                                      98  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H   8-C.sub.6 H.sub.11                                                                    H   130                                      90  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H   8-CH.sub.3                                                                            H   200                                      91  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H   8-WH2C.sub.6 H.sub.5                                                                  H   193                                      92  CH.sub.2 C.sub.6 H.sub.5                                                                N(C.sub.3 H.sub.7).sub.2                                                             OH  H   8-Cl   H   250                                      93  (CH.sub.2).sub.2 N(C.sub.2 H.sub.5).sub.2                                               N(C.sub.3 H.sub.7).sub.2                                                             OH  H   8-Cl   H   220                                      94  (CH.sub.2).sub.3 N(C.sub.2 H.sub.5).sub.2                                               N(C.sub.3 H.sub.7).sub.2                                                             OH  H   8-Cl   H   177                                      95  C.sub.2 H.sub.5                                                                         N(C.sub.3 H.sub.7).sub.2                                                             OH  H   8-Cl   H   230                                      96  CH.sub.3                                                                                 ##STR36##                                                                           OH  H   H      H   >250                                     97  CH.sub.3                                                                                 ##STR37##                                                                           OH  H   8-Cl   H   >250                                     98  CH.sub.3 N(C.sub.5 H.sub.11).sub.2                                                            OH  H   8-Cl   H   185                                      99  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H   8-N(C.sub.2 H.sub.5).sub.2                                                            H   224                                     100  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H                                                                                   ##STR38##                                                                            H   198                                     101  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H   7-N(CH.sub.3).sub.2                                                                   H   220                                     102  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H                                                                                   ##STR39##                                                                            H   105                                     103  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H                                                                                   ##STR40##                                                                            H   48                                      104  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H                                                                                   ##STR41##                                                                            H   156                                     105  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H                                                                                   ##STR42##                                                                            H   104                                     106  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OH  H                                                                                   ##STR43##                                                                            H   150                                     107  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             OC.sub.2 H.sub.5                                                                   H   H      H   240                                                                            (HCl)                                   108  C.sub.2 H.sub.5                                                                         N(C.sub.3 H.sub.7).sub.2                                                             OH  H   8-N(C.sub.2 H.sub.5).sub.2                                                            H   >250                                                                           (HCl)                                   109  CH.sub.2 C.sub.6 H.sub.5                                                                N(C.sub.3 H.sub.7).sub.2                                                             OH  H   8-N(C.sub.2 H.sub.5).sub.2                                                            H   >250                                                                           (HCl)                                   110  H        N(C.sub.3 H.sub.7).sub.2                                                             NH.sub.2                                                                           H   B-N(C.sub.2 H.sub.5).sub.2                                                            H   150                                     111  CH.sub.3 N(C.sub.3 H.sub.7).sub.2                                                             NH.sub.2                                                                           H   8-N(C.sub.2 H.sub.5).sub.2                                                            H   >250                                                                           (HCl)                                   112  H                                                                                        ##STR44##                                                                           NH.sub.2                                                                           H   8-Cl   H   >250                                    113  H        NH.sub.2                                                                             NH.sub.2                                                                           H   8-N(C.sub.2 H.sub.5).sub.2                                                            6-CH.sub.3                                                                         >250                                    114  H        NH.sub.2                                                                             NH.sub.2                                                                           CH.sub.3                                                                           8-N(C.sub.2 H.sub.5).sub.2                                                            6-CH.sub.3                                                                         >250                                    __________________________________________________________________________

Examples of naphthyridine derivatives are mentioned in Table 3.

                                      TABLE 3                                      __________________________________________________________________________      ##STR45##                                                                      ##STR46##                                                                           ##STR47##                                                                              ##STR48##                                                                            ##STR49##                                                                            ##STR50##                                                                           ##STR51##                                                                         ##STR52##                                    __________________________________________________________________________     115                                                                                  ##STR53##                                                                             8-N(C.sub.3 H.sub.7).sub.2                                                           H     OC.sub.2 H.sub.5                                                                    OH 92 (CF.sub.3 COOH)                            116                                                                                  ##STR54##                                                                              ##STR55##                                                                           H     OC.sub.2 H.sub.5                                                                    OH 110                                           117  "                                                                                       ##STR56##                                                                           CH.sub.2 C.sub.6 H.sub.5                                                             OC.sub.2 H.sub.5                                                                    OH 190                                           118  "                                                                                       ##STR57##                                                                           H     OC.sub.2 H.sub.5                                                                    OH >250                                          119  "                                                                                       ##STR58##                                                                           CH.sub.2                                                                             OC.sub.2 H.sub.5                                                                    OH 135                                           120  "                                                                                       ##STR59##                                                                           H     OC.sub.2 H.sub.5                                                                    OH 150                                           121  "                                                                                       ##STR60##                                                                           H     OC.sub.2 H.sub.5                                                                    OH 90                                            122  "                                                                                       ##STR61##                                                                           CH.sub.3                                                                             OC.sub.2 H.sub.5                                                                    OH 220                                           123  "                                                                                       ##STR62##                                                                           H     OC.sub.2 H.sub.5                                                                    OH 230                                           124  "                                                                                       ##STR63##                                                                           CH.sub.3                                                                             OC.sub.2 H.sub.5                                                                    OH 170 (CH.sub.3 COOH)                           125  "       8-Cl  CH.sub.3                                                                             N(C.sub.3 H.sub.7).sub.2                                                            OH 231                                           126  "       8-N(C.sub.3 H.sub.7).sub.2                                                           CH.sub.3                                                                             N(C.sub.3 H.sub.7).sub.2                                                            OH 118                                           127  "                                                                                       ##STR64##                                                                           CH.sub.3                                                                             N(C.sub.3 H.sub.7).sub.2                                                            OH 120                                           128                                                                                  ##STR65##                                                                             7-Cl  H     OC.sub.2 H.sub.5                                                                    OH >250                                          129                                                                                  ##STR66##                                                                             H     CH.sub.3                                                                             N(C.sub.3 H.sub.7).sub.2                                                            OH 175                                           130                                                                                  ##STR67##                                                                             7-Cl  H     N(C.sub.3 H.sub.7).sub.2                                                            OH 225                                           131  "       7-Cl  CH.sub.3                                                                             N(C.sub.3 H.sub.7).sub.2                                                            OH 150                                           __________________________________________________________________________

EXAMPLE 132 1H-3-Amino-2-carbamoyl-8-(N,N-diethylamino)-4-methylpyrrolo[3,2-c ]quinoline ##STR68## a) 4-(carbamoylmethylamino)-3-cyano-6-(N,N-diethylamino)-2-methylquinoline

6.5 g of chloroquinoline, prepared as in Example 8 b), 4.55 g of phenol, 3.7 g of glycinamide hydrochloride and 9.3 ml of triethylamine are heated for 2 hours at 140° C. After cooling, the mixture is acidified by addition of a 0.1N aqueous HCl solution; the crystals obtained are washed with ethyl ether and recrystallised from ethanol. M.p.=225° C.

b) 1 g of the above product is added portionwise to 0.4 g of potassium tert-butoxide in 50 ml of tert-butanol. After stirring for 1 hour, the mixture is poured into cold water and then acidified by addition of a dilute aqueous HCl solution. The hydrochloride of the expected product precipitates after washing with hot acetonitrile; it melts at more than 260° C.

EXAMPLE 133 1H-3-Amino-8-(N,N-diethylamino)-4-ethylpyrrolo[3,2-c]quinoline-2-carboxylic acid ##STR69##

0.5 g of tert-butyl 1H-3-amino-8-(N,N-diethylamino)-4-ethylpyrrolo[3,2-c]quinoline-2-carboxylate (M.p.=240° C.) are added portionwise to an ethyl acetate solution saturated with gaseous hydrochloric acid. The mixture is stirred at room temperature for 48 hours. The crystals obtained are filtered, and washed with acetonitrile and then with isopropanol. M.p.=223° C.

EXAMPLE 134

Ethyl 8-(N,N-diethylamino)-3-hydroxythieno-[3,2-c]-quinoline-2-carboxylate ##STR70## a) 6.1 g of ethyl 6-(N,N-diethylamino)-4-chloroquinoline-3-carboxylate, 2.6 g of ethyl thioglycolate and 3 ml of triethylamine in solution in 50 ml of dimethyl formamide are heated for 3 hours at 70° C. The solvent is evaporated and water and ethyl ether are poured onto the residue; after separation of the ether phase, drying and evaporation of the solvent, the residual oil is chromatographed through silica gel to produce, with a yield of 50%, oily ethyl [4-{6-(N,N-diethylamino)-3-ethoxycarbonyl}quinolyl]-2-thioacetate.

b) 1.6 g of this product in solution in 50 ml of toluene are introduced into a solution of 0.5 g of potassium tert-butoxide in 8 ml of tert-butanol. The mixture is stirred for 12 hours before concentrating to dryness. The residue is taken up in water and the aqueous phase is neutralised by addition of a dilute aqueous hydrochloric acid solution. The yellow precipitate formed is filtered and then recrystallised from a mixture of hexane and isopropyl ether (50/50) to give, with a yield of 45%, the expected product which melts at 142° C.

Examples of thienoquinoline and naphthyridine derivatives appear in Table 4.

                                      TABLE 4                                      __________________________________________________________________________      ##STR71##                                                                      ##STR72##                                                                           ##STR73##                                                                               ##STR74##                                                                           ##STR75##                                                                         ##STR76##                                                                                    ##STR77##                                 __________________________________________________________________________     135                                                                                  ##STR78##                                                                              OC.sub.2 H.sub.5                                                                    OH                                                                                 ##STR79##    >250                                       136                                                                                  ##STR80##                                                                              OC.sub.2 H.sub.5                                                                    OH H             188                                        137                                                                                  ##STR81##                                                                              OC.sub.2 H.sub.5                                                                    OH                                                                                 ##STR82##    168                                        138                                                                                  ##STR83##                                                                              OC.sub.2 H.sub.5                                                                    OH                                                                                 ##STR84##    210                                        139                                                                                  ##STR85##                                                                              N(C.sub.3 H.sub.7).sub.2                                                            OH 8-Cl          146                                        140                                                                                  ##STR86##                                                                              N(C.sub.3 H.sub.7).sub.2                                                            OH 8-N(C.sub.2 H.sub.5).sub.2                                                                   156                                        141                                                                                  ##STR87##                                                                              OC.sub.2 H.sub.5                                                                    NH.sub.2                                                                          8-N(C.sub.2 H.sub.5).sub.2                                                                   186                                        142                                                                                  ##STR88##                                                                              OC.sub.2 H.sub.5                                                                    OH 8-N(C.sub.2 H.sub.5).sub.2                                                                   142                                        __________________________________________________________________________ 

We claim:
 1. A compound of formula ##STR89## in which A represents S;R₁ is selected from the group consisting of OH, (C₁ -C₁₂)alkyl, (C₁ -C₁₂)alkoxy, benzyloxy, phenyl, benzyl (C₁ -C₄)alkyl NZ₁ Z₂, and NZ₁ Z₂ ; R₂ is selected from the group consisting of OH, SH, (C₁ -C₄)alkoxy, (C₁ -C₄)alkylthio, and NZ₁ Z₂ ; R₃ is selected from the group consisting of H, (C₁ -C₄)alkyl, (C₁ -C₄)alkylthio, (C₁ -C₄)alkoxy, phenyl, and benzyl; B is selected from the group consisting of phenyl; pyridyl; phenyl substituted by one or more groups selected from halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, CF₃, CH₂ NZ₁ Z₂, and NZ₁ Z₂ wherein Z₁ and Z₂ are selected, independently of each other, from the group consisting of H, (C₁ -C₆) alkyl, formyl, and benzyl or --NZ₁ Z₂ is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholino, hexahydroazepino, ##STR90## piperazino, piperazino substituted in position 4 by (C₁ -C₈)alkyl, benzyl or diphenylmethyl; and pyridyl substituted by one or more groups selected from halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, CF₃, CH₂ NZ₁ Z₂, and NZ₁ Z₂ wherein Z₁ and Z₂ are selected, independently of each other, from the group consisting of H, (C₁ -C₆)alkyl, formyl, and benzyl, or NZ₁ Z₂ is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholino, hexahydroazepino, ##STR91## piperazino, and piperazino substituted in position 4 by (C₁ -C₈)alkyl, benzyl or diphenylmethyl; or its salt with an acid or a base.
 2. Pharmaceutical composition which comprises a therapeutically effective amount of a compound according to claim 1, optionally in the form of a salt with a pharmaceutically acceptable acid or base together with a pharmaceutically acceptable carrier.
 3. A compound of ##STR92## in which A represents S;R₁ is selected from the group consisting of OH, (C₁ -C₆)alkyl, (C₁ -C₁₂)alkoxy, phenyl, and NZ₁ Z₂ ; R₂ is selected from the group consisting of OH, SH, (C₁ -C₄)alkoxy, (C₁ -C₄)alkylthio, and NZ₁ Z₂ ; R₃ is selected from the group consisting of H, (C₁ -C₄)alkyl, (C₁ -C₄)alkylthio, (C₁ -C₄)alkoxy, phenyl, and benzyl; B is selected from the group consisting of phenyl; pyridyl; phenyl substituted by one or more groups selected from halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, CF₃, CH₂ NZ₁ Z₂, and NZ₁ Z₂ wherein Z₁ and Z₂ are selected, independently of each other, from the group consisting of H, (C₁ -C₄)alkyl, and benzyl or --NZ₁ Z₂ is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholino, hexahydroazepino, ##STR93## piperazino, piperazino substituted in position 4 by (C₁ -C₈)alkyl, benzyl or diphenylmethyl; and pyridyl substituted by one or more groups selected from halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, CF₃, CH₂ NZ₁ Z₂, and NZ₁ Z₂ wherein Z₁ and Z₂ are selected, independently of each other, from the group consisting of H, (C₁ -C₄)alkyl, and benzyl or --NZ₁ Z₂ is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholino, hexahydroazepino, ##STR94## piperazino, and piperazino substituted in position 4 by (C₁ -C₈)alkyl, benzyl or diphenylmethyl; or its salt with an acid or a base.
 4. Pharmaceutical composition which comprises a therapeutically effective amount of a compound according to claim 3, optionally in the form of a salt with a pharmaceutically acceptable acid or base together with a pharmaceutically acceptable carrier.
 5. A compound of ##STR95## in which A represents S;R₁ is selected from the group consisting of (C₁ -C₁₂)alkoxy and NZ₁ Z₂ ; R₂ is selected from the group consisting of OH and NZ₁ Z₂ ; R₃ is H; B is selected from the group consisting of phenyl; phenyl substituted by one or more groups selected from halo and NZ₁ Z₂ wherein Z₁ and Z₂ represent, independently of each other, (C₁ -C₆)alkyl or NZ₁ Z₂ is selected from the group consisting of piperidinyl, piperazino, and piperazino substituted in position 4 by (C₁ -C₈)alkyl; pyridyl; and pyridyl substituted by NZ₁ Z₂ wherein NZ₁ Z₂ is selected from piperazino, and piperazino substituted in position 4 by (C₁ -C₈)alkyl; or its salt with an acid or a base.
 6. Pharmaceutical composition which comprises a therapeutically effective amount of a compound according to claim 5, optionally in the form of a salt with a pharmaceutically acceptable acid or base together with a pharmaceutically acceptable carrier. 